Low concentrations of sorafenib increase dihydrosphingomyelin during antifibrotic processes in human hepatic stellate
Yeonseo Kim1, Baknoon Ham2, Yeojin Kim3
1Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul, 04763, Republic of Korea.
Background:
Inhibiting hepatic stellate cells (HSCs) activation, which represents the initial step of liver fibrosis, is a key strategy for fibrosis treatment. Sorafenib has been repurposed as an antifibrotic agent; however, its reported effects largely rely on cytotoxic mechanisms. The antifibrotic mechanisms induced by minimally cytotoxic sorafenib remain unclear. We aimed to elucidate the dynamic changes in gene expression and lipid metabolites that occur during HSC inactivation using low-concentration sorafenib.
Methods:
Human HSCs (LX-2) were activated by treatment with transforming growth factor (TGF)-β to create a fibrotic environment. The activated cells were treated with sorafenib and then subjected to transcriptomic and lipidomic analyses. In the transcriptomic analysis, statistical significance was assessed using adjusted P-values based on the Benjamini-Hochberg method, whereas significance in the lipidomic analysis was evaluated using MetaboAnalyst.
Results:
During fibrogenesis, we observed upregulation of extracellular matrix-related genes (COL1A1 (P < .001), FN1 (P < .001), THBS1 (P < .001), P4HA3 (P < .01)) and CXCL12 (P < .01), which is an upstream regulator of the Raf/MEK/ERK and PI3K/AKT signaling pathways. Meanwhile, dihydroceramide (dhCer) and dihydrosphingomyelin (dhSM) levels decreased (both P < .001). In contrast, sorafenib-induced antifibrotic conditions significantly reversed these molecular and lipidomic trends (all P < .01).
Conclusions:
In light of the observed trends, we propose that activating the dhSM synthesis pathway may play a regulatory role in fibrosis. Collectively, our study provides novel lipid-based insights into the molecular mechanisms underlying antifibrotic responses.
Insights
Minimally cytotoxic sorafenib reverses liver fibrosis by modulating gene expression and lipid metabolism. Activating dihydro-sphingomyelin synthesis may be a key antifibrotic mechanism.
Area of Science:
- Hepatology and molecular biology
- Fibrosis research
- Lipidomics and transcriptomics
Background:
- Liver fibrosis initiation involves hepatic stellate cell (HSC) activation.
- Sorafenib shows antifibrotic potential, but its minimally cytotoxic mechanisms are unclear.
- Understanding these mechanisms is crucial for developing effective fibrosis treatments.
Purpose of the Study:
- To investigate the gene expression and lipid metabolite changes during HSC inactivation using low-concentration sorafenib.
- To elucidate the antifibrotic mechanisms of minimally cytotoxic sorafenib.
- To identify novel lipid-based targets for fibrosis therapy.
Main Methods:
- Human HSCs (LX-2) were activated using transforming growth factor-beta (TGF-β).
- Activated HSCs were treated with sorafenib.
- Transcriptomic and lipidomic analyses were performed to assess molecular and metabolic changes.
Main Results:
- Fibrogenesis showed increased extracellular matrix genes and CXCL12, with decreased dihydroceramide (dhCer) and dihydrosphingomyelin (dhSM).
- Sorafenib treatment reversed these fibrotic trends, normalizing gene expression and lipid profiles.
- Significant reversal of molecular and lipidomic changes was observed (all P < .01).
Conclusions:
- Activating the dihydrosphingomyelin (dhSM) synthesis pathway may regulate fibrosis.
- The study offers novel lipid-based insights into antifibrotic responses.
- Minimally cytotoxic sorafenib impacts fibrosis through distinct molecular and metabolic pathways.
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